Oral contraception formulations, containing a combination of a progestin and an estrogen, have been known for some time. A number of different regimens for controlling ovulation and conception with these hormones have been developed. Conventional regimens may provide consistent dosage of either an estrogen or progestin or both throughout the period of administration, or they may vary the amount of estrogen or progestin by increasing or decreasing the dosage employed during the period of administration. For instance, U.S. Pat. Nos. 4,616,006 and 4,390,531 disclose triphasic oral contraception regimens wherein the dosage of progestin is varied in three sequences during the 21 day administration period in an effort to minimize side effects and optimize contraceptive activity.
A disadvantage inherent in the current oral contraception regimens is the incidence of abnormal intermenstrual or "breakthrough" bleeding. In general, the intended bleeding pattern with oral contraceptives is usually predictable and occurs during the seven day drug free interval following 21 days of active drug administration. Breakthrough bleeding refers to incidences of bleeding or spotting during the 21 day administration period. Breakthrough bleeding or spotting is reported to occur in about 20-30% of women. The incidence of breakthrough bleeding is the highest during the first few months of treatment and appears to be related to the dose and nature of the hormonal components as well as idiosyncratic responses. Another related problem with conventional oral contraceptive regimens is the occurrence of early withdrawal flow which is any bleeding or spotting during the drug administration interval which continues without interruption into the period wherein drug administration is withdrawn. Since discontinuation of a method of contraception because of abnormal intermenstrual bleeding continues to be an important factor leading to drug discontinuation and unintended pregnancy, there is a need for combined oral contraceptive formulations that meet the various clinical demands of the user and which provide the most acceptable pattern of bleeding.
Extended use regimens have been investigated wherein oral contraceptives are administered for up to three months between cycles. A three month trial of a regimen of oral contraceptives that reduces the frequency of menstruation was first described by Loudon, NB, Br.Med.J. 1977;2:487-90. The advantages of such regimens are that they offer freedom from menstrual flow and premenstrual symptoms for extended periods of time and are generally easier to follow. Such extended use regimens may also have therapeutic use in dysmenorrhea, menorrhagia, premenstrual-type symptoms and menstrual migraine. Sulalc et al., Obstet-Gynecol 1997;89: 179-83 in a restropective analysis, reports that 74% of the patients treated with 6 weeks of continuous active pills were stabilized and that the extended oral contraceptives regimen delayed the onset and severity of reported complaints. However, such extended use regimens are hampered by a high incidence of breakthrough bleeding, which is a common cause for discontinuation of the regimen.
Accordingly, there is a need for an oral contraceptive treatment regimen which reduces the incidence of bleeding abnormalities. As will be seen, there is also a related need for an oral contraceptive treatment regimen which achieves this reduction in the incidence of bleeding abnormalities while exhibiting a favorable effect on endometrial morphology.
There is also a need for an extended use oral contraceptive treatment regimen which achieves effective contraception but which exhibits a reduced incidence of bleeding abnormalities.
Different progestins in combined oral contraceptives appear to be associated with different bleeding patterns. While the mechanism for bleeding irregularities is still poorly understood, applicants have observed different patterns of breakthrough bleeding and spotting in comparative studies of the combination oral contraceptives norgestimate/ethinyl estradiol versus levonorgestrel/ethinyl estradiol. The variation in the bleeding patterns was more pronounced in those patients who were not taking oral contraceptives in the cycles prior to the study. In general, the overall proportions of breakthrough bleeding episodes were similar, but the patterns differed.
Progestational agents also differ in their effects on the endometrium. This can range from a proliferative or secretory endometrium to a non-vascular or atrophic condition which can resemble the postmenopausal histological structure. These effects are manifested by morphological changes in the endometrial glands, spiral capillaries, endometrial stroma and epithelial tissues. Cycle control during oral contraceptive use is related to the pattern of endometrial maturation. Thus, depending on the progestational agent used, one can detect histological differences between preparations which could subsequently influence the bleeding patterns. The endometrial morphology appearance has been observed to be different between norgestimate and levonorgestrel formulations. After six months treatment with norgestimate/ethinyl estradiol, well preserved lining epithelium was observed corresponding to midcycle or early secretory phase of the normal menstrual cycle. (Rabe, T. et al, Gerbutsch Fauenheilk 1986,46:883).
Norgestimate was found to have an endometrial sparing effect in primates in comparison to other progestins. (Wilborn, WH et al, 1984, 4th Annual Meeting of Ala.
Academy of Science, Tuscaloosa, Ala.). In general, the findings during treatment in humans with norgestimate containing oral contraceptives indicate a secretory transformation of well developed endometrium which was found however incapable of supporting an implanted blastocyte. In contrast, women treated with levonorgestrel containing oral contraceptives generally exhibit atrophic endometrial appearance with diminished gland diameter and glandular epithelial.